Lithium

• Since sodium is so pervasive in the human body and lithium can also alter these processes, it has been very difficult to identify the key mechanism of action of lithium in regulating mood.
  • For example, there is some evidence that people with bipolar illness have higher intracellular concentrations of sodium and calcium than controls, and that lithium can reduce these.
• Lithium is hypothesized to modulate dopaminergic, glutamatergic and gabaergic neurotransmission.^[1] Lithium alters sodium transport across the cell membranes of nerve and muscle cells. There are multiple proposed mechanisms for lithium in its role in treatment of mania and bipolar disorder, including:
  • Inhibition of inositol monophosphatase intracellular signaling
  • Altering metabolism of neurotransmitters including catecholamines and serotonin
  • Effects neural plasticity through effects on glycogen synthetase kinase-3β , cyclic AMP- dependent kinase, protein kinase C
  • Increasing cytoprotective proteins
  • Activating signaling cascade used by endogenous growth factors
  • Potentially inducing neurogenesis at synaptic sites.
• Subsequent actions by lithium include:
  • Increasing synthesis of serotonin by increasing tryptophan reuptake in synaptic terminals
  • Downregulation of 5-HT1A, 5-HT1B, 5-HT2 receptors
  • Increasing rate of synthesis of norepinephrine
  • During manic episodes, lithium is thought to reduce the excretion of norepinephrine
  • During manic episodes, lithium is thought to increase excretion of norepinephrine metabolites

Most risk factors for developing lithium toxicity involve changes in sodium levels or the way the patient's body handles sodium. For example low salt diets, dehydration, drug-drug interactions (see below) and illnesses like Addison’s disease can lead to toxicity. Patients should be well-informed of these risk factors when starting treatment. Also, always remember to treat the patient and not the number! Serum lithium concentrations do not always reliably correlate with the clinical severity of toxicity.^[2]

• Bipolar I disorder
  • Lithium is effective in the treatment of moderate to severe mania (NNT = 6), and for prophylaxis of bipolar affective disorder (reduces both the number and the severity of relapses, NNT = 10-14).^[3]
  • Lithium is more effective at preventing manic than depressive relapse. Lithium also offers some protection against antidepressant‐induced hypomania.
  • It is generally clinically appropriate to initiate prophylactic treatment after a single manic episode that was associated with significant risk and adverse consequences, or in bipolar I illness, two or more acute episodes.
• Bipolar II disorder
• Major depressive disorder, most commonly as an adjunctive medication

• Lithium comes in oral and liquid formulation.

• Intermittent treatment with lithium may worsen the natural course of bipolar illness. A much greater than expected incidence of manic relapse is seen in the first few months after discontinuing lithium,^[12] even in patients who have been symptom free for as long as 5 years.^[13]
• Some recommendations have been made that lithium treatment should not be started unless there is a clear intention to continue it for at least 3 years.^[14]
  • This advice has obvious implications for initiating lithium treatment against a patient’s will (or in a patient known to be non‐adherent with medication) during a period of acute illness.

• Sodium balance (i.e. - salt intake) can have an impact on lithium levels. When there is sodium depletion (i.e. - hyponatremia or low sodium intake), lithium undergoes higher reabsorption, resulting in higher serum levels. Conversely, when there is high sodium intake, there is decreased lithium reabsorption, resulting in lower serum levels.

• Lithium may have neuroprotective effects, possibly mediated through its effects on N‐methyl‐D‐aspartate (NMDA) pathways.^[15] It is important to note that the literature suggesting these neuroprotective effects are based on in vitro and animal studies, and not in humans.^[16]
• Increasingly, some observational and retrospective studies have shown a lower risk for dementia in individuals with mood disorders treated with lithium.^[17]

• Lithium is one of two psychotropics (the other is clozapine) that has evidence that it reduces the risk of suicide.^[18][19][20]
  • The finding of anti-suicidal effects is much stronger for lithium than clozapine.^[21][22]
• The mechanism of this is still under investigation, but theories focus largely on its effects on neurotransmitters.
  • The most common hypothesis is that lithium leads to a decrease in impulsivity and aggression via several influences within the nerve cell.^[23]
• A more recent meta-analysis challenged the notion of lithium reducing suicide risk.^[24][25]
• Another study showed that the use of lithium as an augmentation agent (i.e. - in addition to a primary medication) at sub-therapeutic doses (<0.54) did not reduce the overall incidence of suicide-related events compared to placebo.^[26]

• Lithium should not be used during first trimester of pregnancy, due to increased risk for Ebstein's anomaly (cardiac malformation)
  • Although traditionally considered an absolute contraindication, there is some argument from certain clinicians that the risks and benefits should be discussed with the individual patient (e.g. - high risk for relapse or severe deterioration when off lithium).^[27]
• Severe renal impairment
• Cardiovascular disease with arrythmias (can cause reversible T-wave changes, or unmask Brugada syndrome)
• Addison's disease
• Untreated hypothyroidism or thyroid disorder

• Mild renal disease

• Lithium tremors are classified as a postural tremor and produced by voluntary maintenance of a particular posture held against gravity typically at a frequency of 8 to 12 Hz in the hands.^[28]
  • The prevalence of lithium tremors varies widely depending on the study, ranging from 4% to 65% (average 27%).^[29]
  • For most patients a lithium tremor is tolerable and does improve spontaneously over time.
• Lithium tremors can be both non-toxic (i.e. - from chronic lithium use), and toxic (i.e. - a sign of acute intoxication)
  • Tremors that begin at the start or during titration of lithium treatment usually suggests lithium tremor. Serum lithium concentration should always be checked during these periods to rule out lithium toxicity.
• Lithium tremors can be managed with beta blockers (e.g. - propranolol), primidone, gabapentin, and topiramate. Benzodiazepines are not generally recommended due to the risk for falls, dependence, and cognitive impairment.

• Psoriasis, acne, alopecia can also occur (hair often regrows with or without stopping lithium).

• Nephrogenic diabetes insipidus (NDI) is characterized by intense thirst and polyuria with inability to concentrate urine due to a reduction of ADH (antidiuretic hormone, also known as vasopressin). Chronic lithium use can cause ADH resistance in the kidneys, leading to decreased urinary concentrating capacity. NDI is usually reversible in the short to medium term but may be irreversible after long‐term treatment with lithium (i.e. - over 15 years).
• Lithium levels that are >0.8 mmol/L are associated with a higher risk of nephrotoxicity. NDI can be diagnosed with a water restriction test, and considered positive when there is no change in urine osmolality despite restriction.
• Management includes discontinuing lithium, reducing the daily dosage, or reducing the dosing schedule. Diuretics can also be used to treat NDI, but requires close monitoring of lithium and potassium levels.^[30]

• Long-term lithium use increases the risk of hypothyroidism. In middle‐aged women, the risk may be up to 20%, while up to 30% develop asymptomatic elevated TSH. Lithium-related hypothyroidism can be easily treated with levothyroxine.
• Some clinicians suggest testing for thyroid autoantibodies in middle-aged women before starting lithium (to better estimate the risk of hypothyroidism) and for monitoring more frequently in the first year of treatment.^[31]

• Lithium increases the risk of hypercalcemia and hyperparathyroidism (prevalence of ~5%).^[32] Up to 10% of patients on long-term lithium treatment develop hypercalcaemia and hyperparathyroidism, and this is even higher in the geriatric population.^[33]
• These two conditions are frequently under-diagnosed in psychiatric practice and there are recommendations that calcium levels should be monitored in patients on long‐term treatment.^[34] Sequelae of long-term chronic hypercalcemia includes renal stones, osteoporosis, dyspepsia, hypertension and renal impairment.
• Symptoms of hypercalcemia (and consequently hyperparathyroidism) can also mimic as psychiatric disorders, with disturbances of mood, energy, and cognition.

• Lithium can cause leukocytosis, neutrophilia, and increased platelet counts.^[35]

• Lithium can cause changes on ECG, including QTc prolongation, T-wave flattening or inversion, bradycardia, sick sinus node syndrome, and AV block.

• Long-term use of lithium (i.e. - over decades) has been linked to chronic kidney disease (CKD) and end-stage renal disease (ESRD). The estimated risk of developing CKD and progressing to ESRD is around 1.5% in long-term lithium users.^[37] Importantly, the majority of patients on long-term lithium treatment do not appear to develop impaired renal function.^[38]
  • More recent studies have found that the trajectory of kidney function decline varies widely between individuals on lithium long-term. In patients with a fast trajectory, a trade-off is required between continuing lithium to treat mental health problems and discontinuing lithium for the sake of renal health.^[39]
  • On a population level, cohort studies show that lithium use is associated with an additional eGFR deterioration of 0.54mL/min/1·73m² per year.^[40]
• Routine monitoring for both creatinine and eGFR is thus important for patient on lithium. There are no strict eGFR cut-offs for discontinuing lithium if there is concern about nephrotoxicity (CKD is defined as eGFR <60mL/min). Guidelines suggest referring to nephrology if:^[41]
  • eGFR falls by >5 mL/min in 1 year, or >10 mL/min within 5 years, or
  • eGFR <45mL/min in two consecutive readings, or
  • Clinician is concerned for other reasons

• Interestingly, drinking caffeine can reduce lithium levels, as it is thought to increase renal lithium clearance.^[42]

• For geriatric patients, lithium levels should be <0.8 mmol/L where possible (0.4 to 0.6 for depression, and 0.4 to 0.8 for mania/hypomania). Once daily dosing is best, and it is best to start at a lower dose of 150 mg per day.
  • Typically, 450 mg per day is enough to reach a therapeutic level for geriatric patients. In some cases, a therapeutic effect is achieved between 0.2 to 0.6 mmol/L, this is because there is a lower correlation between serum lithium levels and cerebrospinal levels in older age (due to a leakier blood brain barrier).
• Make sure that chronic conditions like diabetes, hypertension, and cardiovascular risk factors are well-controlled. The medical risks and benefits of lithium needs to be carefully weighted in older users of lithium, particularly when chronic kidney disease is more common in this population. Lithium overall remains an under-utilized treatment in this population despite overwhelming evidence for it use, its possible neuroprotective effects, and decreased mortality rates.

• Lithium should be held 24 hours prior to delivery due to risks of massive fluid shifts from delivery causing lithium toxicity
• For pregnancy women on lithium, post-delivery, it is essential to monitor the infant for signs of hypotonia and “floppy baby syndrome” in the first 48 hours.
• Breastfeeding is also not recommended as lithium is expressed in the breast milk

• Lithium levels and renal function should be closely monitored in those with renal disease.